Drug-loaded pellets or beads are specialized drug delivery systems that have been used successfully to develop products that control the release of active ingredients in the gastrointestinal tract at predetermined rates.
A number of pellet or bead manufacturing processes have been developed for the production of pharmaceutical products. The most popular processes utilize organic or aqueous solvents to facilitate pellet production, and can be classified into three categories: solution/suspension layering; powder layering; and wet granulation/extrusion/spheronization. Typically, pellet cores are dried and coated with functional coatings, films or layers to generate controlled release pharmaceutical formulations that are subsequently filled in hard shell gelatin capsules or compressed into tablets.
Solution/suspension layering is generally utilized only when pellets with a low drug loading capability are desired; for high drug loading, the processing times tend to be too long. The layering process is relatively simple and utilizes any conventional coating equipment, although fluid bed machines, due to their high drying efficiency, are the equipment of choice. Powder layering, probably the oldest pharmaceutical pelletization process, utilizes equipment that range from convention coating pans to highly specialized centrifugal fluid bed equipment. In this process, the powder is layered on starter seeds with the simultaneous application of a binder solution.
Extrusion/spheronization is a process where the active ingredient and excipients are sequentially blended, wet-granulated, extruded and spheronized to form pellets. Spheronization is a multi-step process that is employed mainly when pellets with very high drug loading capacities are needed to accommodate high dose products.
Recently, attempts have been made to prepare spherical pellets by melt-spheronization using heat-jacketed spheronizers or marumerizers that are commonly used in wet extrusion/spheronization. For example, published International Patent Application Nos. PCT WO 02/35991 A2 and WO 93/07859 disclose hot-melt extrusion/spheronization processes for manufacturing spherical particles, e.g., active agent-containing pellets or beads. Both applications assert that the processes can be continuous while also eliminating the need for water or organic solvents. However, in both inventions the extrusion and cutting steps are continuous while the spheronization step is in a batch mode. This is made clear in several of the Examples set forth in PCT application WO 02/35991 A2 where it is described that the pellets are cooled to room temperature after being cut in the pelletizer and before being transferred to the spheronizer. Also, it is implicit in WO 93/07859 that the spheronization step is a batch process. This is evident by the use of a Luwa spheronizer which is batch process equipment whose output can only increase by increasing the size of the equipment as opposed to, for example, increasing the processing time as is the case with continuous processors. Thus, unlike the present invention, the processes described in the PCT applications are batch-based and hence prone to the shortcomings associated with typical batch manufacturing processes. Moreover, melt spheronization using conventional marumerization equipment often leads to tacky pellets that tend to agglomerate during manufacturing. This problem could be alleviated by the addition of dusting powder, a procedure that may not necessarily satisfy the requirements of process validation.
The present invention relates to a novel continuous melt spheronization apparatus and process whereby an active ingredient and appropriate excipients are blended and formed into spherically-shaped particles or pellets. The present invention eliminates the need for water or organic solvents and provides particles that fall within a narrow particle size range. As a result, water sensitive drugs and materials can also be employed without running the risk that the drug will be affected by the presence of the solvent. The pellet cores may be further coated with materials such as sugars, polymers, waxes and the like. The coatings of the present invention may also be tailored to the particular need for drug delivery and may be designed to produce immediate, enteric or modified release products.